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An investigation of the clinical profile and extent of Long QT Syndrome (LQTS) associated with the KCNQ1-A341V mutation in South Africa and with the KCNH2-A1116V mutation in an Italian family and the role that autonomic nervous system (ANS) activity and genetics play in clinical variability

Background
Although great progress has been made in defining genes conferring the majority of genetic risk in
Long QT Syndrome (LQTS) patients, there remains a substantial challenge to explain the widely
observed variability in disease expression and phenotype severity, even among family members,
sharing the same mutation. Identifying clinical and genetic variables capable of
influencing/predicting the clinical phenotype of LQTS patients would allow a more accurate risk
stratification, important for determining prognosis, selecting patients for the most appropriate
therapy, and counseling asymptomatic mutation carriers (MCs).
To address these questions an Italian LQT2 family and a South African Founder LQT1 population
have been used.
Methods and Results
Italian LQT2 family. The proband, a 44-yr-old white woman, presented with ventricular fibrillation
and cardiac arrest. Intermittent QT prolongation was subsequently observed and LQT2 was
diagnosed following the identification of a missense KCNH2 mutation (A1116V). The proband also
carried the common KCNH2 polymorphism K897T on the non-mutant allele. Relatives who carried
A1116V without K897T were asymptomatic but some exhibited transient mild QTc prolongation
suggesting latent disease. Expression studies in Chinese Hamster Ovary (CHO) cells, demonstrated
that the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the
A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband
carrying both alleles.
South African LQT1 population. The study population involved 320 subjects, 166 MCs and 154 non
mutation carriers (NMCs). Off ß-blocker therapy, MCs had a wide range of QTc values (406-676
ms) and a QTc>500 ms was associated with increased risk for cardiac events (OR=4.22; 95%CI
1.12-15.80; p=0.033). We also found that MCs with a heart rate <73 bpm were at significantly
lower risk (OR=0.23; 95%CI 0.06-0.86; p=0.035). In a subgroup of patients Baroreflex Sensitivity (BRS) was determined both in presence and absence of ß-blocker therapy. BRS, analyzed in
subjects in the 2nd and 3rd age quartiles (age 26-47) to avoid the influence of age, was lower among
asymptomatic than symptomatic MCs (11.8±3.5 vs 20.1±10.9 ms/mmHg, p<0.05). A BRS in the
lower tertile carried a lower risk of cardiac events (OR 0.13, 95%CI 0.02-0.96; p<0.05). This study
also unexpectedly determined that KCNQ1-A341V was associated with greater risk than that
reported for large databases of LQT1 patients: A341V MCs were more symptomatic by age 40
(79% vs 30%) and became symptomatic earlier (7±4 vs 13±9 years), both p<0.001. Accordingly,
functional studies of KCNQ1-A341V in CHO cells with KCNE1, identified a dominant negative
effect of the mutation on wild-type channels.
Conclusion
Our findings indicate that risk stratification for LQTS patients must be more individually tailored
and may have to take into account the specific mutation and probably additional clinical and genetic
variables capable of influencing/predicting the clinical phenotype of LQTS patients. As a matter of
fact, we have provided evidence that a common KCNH2 polymorphism may modify the clinical
expression of a latent LQT2 mutation and the availability of an extended kindred with a common
mutation allowed us to highlight that KCNQ1-A341V is associated with an unusually severe
clinical phenotype and to identify two autonomic markers, HR and BRS, as novel risk factors.